European Journal of (2011) 164 937–942 ISSN 0804-4643

CLINICAL STUDY Low plasma triiodothyronine levels in failure are associated with a reduced anabolic state and membrane damage Gabriela Brenta, Jorge Thierer1, Marcela Sutton1, Adriana Acosta1, Nora Vainstein1, Fernando Brites2, Laura Boero2, Leonardo Go´mez Rosso2 and Stefan Anker3,4 Department of Endocrinology, Cesar Milstein Hospital, La Rioja, CABA 1221, Buenos Aires, Argentina, 1Cardiovascular Institute of Buenos Aires (ICBA), Buenos Aires, Argentina, 2School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina, 3Applied Cachexia Research, Department of Cardiology, Charite´ Universita¨tsmedizin Berlin, Campus Virchow-Klinkum, Berlin, Germany and 4Centre for Clinical and Basic Research, IRCCS San Raffaele, Rome, Italy (Correspondence should be addressed to G Brenta; Email: [email protected])

Abstract

Background: Low plasma triiodothyronine (T3) levels are considered a prognostic predictor of death in heart failure (HF) patients. Aim: To study an association between plasma T3 levels and several cardiac, neurohormonal, and metabolic markers of HF. Methods: A total of 133 ambulatory HF patients (114 males; mean age 63.2 years) with left ventricular ejection fraction !40% were enrolled. TSH, total tetraiodothyronine (T4) and T3, N-terminal pro-brain (NT-proBNP), and other cardiac and metabolic parameters were measured. The lowest tertile of T3 (group 1) was compared against the two upper ones (group 2). Results: In simple logistic regression, the lowest T3 tertile was associated with more advanced HF disease status: older (age: odds ratio (OR)Z1.05; confidence interval (CI) 95% 1.01–1.09, PZ0.004), lower functional capacity (walking test: ORZ0.996; CI 95% 0.993–0.999, PZ0.008), higher NT-proBNP (ORZ1.64; CI 95% 1.19–2.27, PZ0.003) and levels (ORZ1.07; CI 95% 1.02–1.11, PZ0.004), lower DHEAS log-transformed (ORZ0.50; CI 95% 0.31–0.80, PZ0.004), and the presence of lower phase angle values as measured by body bioelectrical impedance analysis (ORZ3.18; CI 95% 1.50–6.71, PZ0.04) and worse renal function (ORZ0.96; CI 95% 0.94–0.98, PZ0.003). T3 levels in the lowest tertile were independently associated with low phase angle values (ORZ2.95, CI 95% 1.16–7.50, PZ0.02) and the log transformation of DHEAS (ORZ0.56; CI 95% 0.32–0.97, PZ0.04). Conclusion: We have demonstrated an association between plasma T3 levels in the lower range and other deranged hormonal and metabolic parameters in HF patients.

European Journal of Endocrinology 164 937–942

Introduction Several changes consistent with the downregulation of the signaling system take place and non-thyroidal illness in the advanced failing heart and postinfarcted syndrome are the terms currently used to define a myocardium. This hypothyroid phenotype includes a condition characterized by an impairment of the lower expression of thyroid hormone -a1 (TRa1 –pituitary–thyroid axis present in most or THRA), sarcoplasmic reticulum calcium ATPase critically ill patients. A fall in serum triiodothyronine (SERCA2 or ATP2A2), and higher expression of b (T3), also known as low T3 syndrome, is one of the most myosin genes (7–9). Although these changes in cardiac common changes observed (1–3). This pathological phenotype might be due to low circulating levels of process has been found to be present in about 30% thyroid in HF, impaired thyroid hormone of congestive heart failure (HF) patients. Those signaling might also result from the re-expression of patients classified as New York Heart Association type 3 (D3), the local thyroid hormone (NYHA) functional class III–IV (4) have shown a inactivating , in cardiomyocytes (10, 11). higher prevalence of low T3 levels. Furthermore, the Reversal of this hypothyroid phenotype with physio- low T3 syndrome in HF is considered a predictor of logical replacement of T3 might prove beneficial as been death (5, 6). shown in animal models of HF where left ventricular

q 2011 European Society of Endocrinology DOI: 10.1530/EJE-11-0094 Online version via www.eje-online.org

Downloaded from Bioscientifica.com at 09/28/2021 02:09:36PM via free access 938 G Brenta and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2011) 164 contractile performance was improved (12) or with , and cholesterol panels were determined. We ventricular ischemia where early long-term L-T3 measured high-sensitivity C-reactive protein (hsCRP), replacement has been shown to preserve the mito- uric acid, , adiponectin, albumin, and chondria and prevent ischemic cardiac remodeling (13). DHEAS, and N-terminal pro-BNP (NT-proBNP). Moreover, studies of short-term T3 replacement in For determination of hsCRP, leptin, adiponectin, patients undergoing coronary artery bypass surgery NT-proBNP, cortisol, and DHEAS, all the samples were and in patients with advanced HF have also demonstrated processed in the same assay. a hemodynamic benefit with such therapy (14–16). hsCRP was determined by Tina-quant CRP (Latex, It can be argued that low T3 levels present in HF Mannheim, Germany) high-sensitive immunoturbidi- might not just indicate disease progression but they metric assay (Roche Diagnostics) in a Hitachi 917 might have a pathophysiological role. This might be autoanalyzer. The intra assay coefficient of variation explained by the direct effects of low T3 levels in the (CV) was 0.43%. cardiovascular system and/or through a possible Leptin was measured by IRMA (Active Human Leptin interaction with catabolic and inflammatory par- IRMA, Diagnostic System Laboratories, Inc., Webster, ameters also present in HF (17). This is in line with TX, USA). The intra assay CV of the assay at 3.0 ng/ml the idea that the pathophysiological phenomenon was 3.9% and at 12 ng/ml was 1.7%. behind HF initially involves a compensatory activation Adiponectin was determined by enzyme immunoas- of hormonal, immunological, and proinflammatory say (Quantikine Human Adiponectin/Acrp30 Immu- systems. However, a later phase ensues where all of noassay. R&D Systems, Inc., Minneapolis, MN, USA). these compensatory responses eventually become The intra assay CV of the assay at 19.8 mg/ml was 2.5%. maladaptive (18). The use of markers such as brain NT-proBNP was determined by immunoassay natriuretic peptide (BNP) (19) or adiponectin (20), (proBNP Elecsys Roche Diagnostics GmbH). The intra which provide prognostic information of adverse out- assay CV was 2.7%. come in HF, is well established. However, an interaction Plasmatic and urinary cortisol levels were evaluated between T3 levels and catabolic parameters present in by immunoassay (Access Cortisol, Beckman Coulter, HF still remains a matter of interest for further research. Fullerton, CA, USA). The intra assay CV was 6.4% for In this study, we explored a possible association of low plasmatic and 4% for urinary-free cortisol. T3 circulating levels with some of the hemodynamic, DHEAS was assessed by RIA (Coat-A-Count DHEAS- neurohormonal, and metabolic prognostic parameters SO4 Diagnostic Products Corporation, Los Angelas, CA, present in congestive HF patients. USA). The intra assay CV was below 5.3%. TSH, T3, and T4 were determined by electrochemilu- minescence immunoassay (Elecsys 1010-ROCHE Diag- nostic). TSH reference values were 0.3–5.0 mIU/ml. Materials and methods Intra assay CV% was 2% and inter assay CV was 3.7% using a human serum sample with 0.9 mIU/ml (EP5- Subjects Modified protocol of National Committee of Clinical We prospectively included 151 consecutive ambulatory Laboratories Standards, NCCLS). Analytical sensitivity patients with systolic HF referred to our institute between of the method was: 0.005 and functional sensitivity was May 2005 and March 2007 in the MIMICA study, 0.014 mIU/ml. designed to explain the relationship between metabolic T4 reference values were 4.5–13.0 mg/dl. Intra assay and inflammatory markers and severity of disease (21). CV% was 2.9% and inter assay CV was 3.9% using a All patients had left ventricular ejection fraction (LVEF) human serum sample with 9.0 mg/dl in six daily assays %40% and were in a stable condition (not hospitalized during 10 days (EP5-A, NCCLS). because of decompensated HF, nor required a visit to T3 reference values were 0.8–2.0 ng/ml. Intra assay emergency department or a raise of the diuretic dose) CV% was 4.1% and inter assay CV was 4.9% using a at least for 3 months prior to their inclusion in the study. human serum sample with 2.1 ng/ml in six daily assays After excluding overt hypothyroid and hyperthyroid during 10 days (EP5-A, NCCLS). Analytical sensitivity patients, 133 patients remained to be included in the was 0.195 ng/ml. present analysis. Overt was defined as In non-diabetic patients, resistance was TSHvaluesO5.0 mIU/mlandtotaltetraiodothyronine(T4) calculated by the homeostasis model assessment index values !4.5 mg/dl. Overt was defined for insulin resistance (HOMA-IR)Z(fasting plasma as TSH values !0.3 mIU/ml and T4 values O13 mg/dl. glucose (mg/dl)!fastingplasmainsulin(mIU/ml))/ (18!22.5). Blood sampling and analysis Echocardiography Following a 12 h overnight fast, venous blood was obtained from the antecubital vein. Hematological The acquisition of echocardiographic data was perfor- parameters, urea, creatinine, glycemia, baseline insulin, med using the Philips iE33 Ultrasound.

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M-mode left ventricular dimensions were obtained in the Declaration of Helsinki. The protocol was approved from the parasternal long-axis view following the by the institutional ethics committee and signed standard Echocardiography American guidelines, deter- informed consent was obtained from each participant. mining left ventricle diastolic and systolic diameters, In order to explore the relationship between low T3 interventricular septum, posterior wall, and aortic root. values and the baseline parameters, the population was Left atrial area was traced in apical four-chamber view. divided into tertiles of T3, and the lowest tertile (group Ventricular function was performed in four-chamber 1) was compared against the two upper ones (group 2). apical view: the endocardial border was manually traced in end systole and end diastole and using the Statistical analysis Simpson method (biplane), left ventricular end diastolic volume, left ventricular end systolic volume, and Categorical variables are presented as percentages and ejection fraction were assessed. continuous variables as meanGS.D. when their distri- bution was normal, or median and interquartile range when it was not. Six minutes walking test Comparisons between the two groups were performed 2 Functional capacity was assessed with the 6 min by Student’s t-test (continuous variables) or c test walking test, performed in a flat straight 30 m corridor. (categorical variables). Simple and multiple logistic The test was conducted under the control of an regressions were performed to define variables signi- experienced physician who encouraged the patients to ficantly associated with the lowest tertile of T3. walk in the corridor at a higher rate from one extremity Logarithmic transformation was performed to achieve to the other as much time as possible. Patients were a normal distribution for skewed variables and to allowed to stop if necessary but were urged to resume the introduce them in the multivariable analysis. walk as soon as they recovered. Baseline and final heart Statistical analysis was performed with Stata 10 rate and systolic were recorded. The package (StataCorp, College Station, TX, USA). distance walked in 6 min (6MWD) is expressed in meters. Results Bioelectrical impedance analysis In every patient, body composition (muscle mass, fat Baseline characteristics mass content, and total, intra- and extracellular water) Of the 133 patients, 114 (85.7%) were males and mean was assessed by body bioelectrical impedance analysis age was 63.2G11.5 years; 9.7% were cigarette (BIA). All the tests were performed by the same skilled smokers, 24.8% diabetic, 54.9% had arterial physician using a tetrapolar and multiple frequency equipment (four-channel bioimpedance meter BioScan MSR-916, Maltron International Ltd, Rayleigh, UK). Table 1 Comparison of demographic parameters, clinical charac- BIA has been validated as a suitable method to teristics, heart failure disease status, and use of drugs between group 1 and group 2 patients. determine body composition and is well correlated with dual-energy X-ray absorptiometry (22).The Group 1 Group 2 method is based on the resistance encountered through nZ45 nZ88 P value water and the body tissues during low-intensity electric Male sex (%) 88.8 81.8 0.29 current passage. The two electrodes are placed on the Age (years) 67.2G11.6 60.9G11.8 0.002 palm and wrist as well as the other two electrodes on Diabetes (%) 28.9 23.8 0.53 the foot sole and ankle; all electrodes are placed on the Hypertension (%) 46.6 55.6 0.32 right side of the body. In order to perform the test, the Ischemic etiology (%) 62.2 48.8 0.14 NYHA III–IV (%) 35.5 22.7 0.11 patient has to remain lying down on the supine Atrial fibrillation (%) 15.5% 6.8% 0.11 position, in a fasted condition for the last 6 h and b-Blockers (%) 95.5% 89.8% 0.25 having avoided strenuous exercise within the last 12 h. ACEI–ARB (%) 73.3% 85.2% 0.10 Determination of phase angle, a marker of membrane Amiodarone (%) 46.6% 31.8% 0.09 Diuretics (%) 93.3% 75% 0.01 damage, was also assessed (22). Low phase angle, a Digitalis (%) 28.8% 19.3% 0.21 marker of membrane damage, was defined as !5.5 LVEF 28.2G7.8 28.4G7.7 0.90 degrees in women or !6.5 degrees in men. 6 min walking test (mts) 251G132 320G136 0.006 Resting metabolic rate (kcal) 1416G208 1487G244 0.09 Fat-free mass (%) 70.6G7.4% 68.9G7.9 0.22 Protocol Phase angle (degrees) 6.5G2.2 7.2G2.1 0.08 Low phase angle (%) 62.2 34.1 0.002 All tests were carried out within 5 days of inclusion, BMI, body mass index; NYHA III–IV, New York Heart Association functional at the Instituto Cardiovascular de Buenos Aires. class III–IV; ACEI, angiotensin-converting ; ARB, angioten- The investigation complied with the principles outlined sin receptor blocker; LVEF, left ventricular ejection fraction.

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Table 2 Comparison of biochemical values between group 1 and diuretics, and a trend to be more symptomatic and more group 2 patients. frequently treated with amiodarone. They presented with less than 6 min walking distance, worse renal Group 1 Group 2 P function, lower levels of DHEAS, and higher NT-proBNP nZ45 nZ88 value and adiponectin values. Their phase angle was lower, Hemoglobin (g/dl) 13.8G1.5 14.1G1.5 0.26 and the prevalence of low phase angle was higher. LVEF, GFR (ml/min/1.73 m2)52G18 62G17 0.002 WBC count 7.2G1.9 7.3G1.4 0.74 left ventricular diameters and volumes, and E/A relation (1000/mm3) were not significantly different among tertiles. G G Na (meq/l) 140 4 141 3 0.16 In simple logistic regression (Table 3), the lowest T3 K (meq/l) 4.7G0.4 4.7G0.4 0.63 tertile was associated with more advanced HF disease HOMA-IR 2.3G1.5 3.1G2.5 0.09 Cholesterol (mg/dl) 188G41 199G60 0.32 status: older, lower functional capacity, higher Leptin (ng/ml) 9.5G6.8 9.7G6.1 0.86 NT-proBNP and adiponectin levels, lower DHEAS log- Cortisol (mg/dl) 16.9G4.9 16.1G4.8 0.30 transformed, and the presence of low phase angle values DHEAS (mg/dl) 40 (24–70) 63 (40–99) 0.003 hsCRP (mg/l) 2.7 (1.3–5.4) 2.7 (1.3–5.7) 0.96 and worse renal function. NT-proBNP (pg/ml) 1350 (956–2676) 794 (235–1703) 0.0004 In multiple logistic regression (Table 3), the lowest Adiponectin (mg/ml) 16.8G7.4 12.3G7.9 0.002 tertile of T was independently associated with low G G 3 T3 (ng/ml) 0.83 0.07 1.14 0.16 0.0001 phase angle values (odds ratio (OR)Z2.95, confidence T4 (mg/dl) 8.6G1.8 7.9G1.3 0.028 TSH (mIU/ml) 2.6G2.3 3.3G2.5 0.12 interval (CI) 95% 1.16–7.50, PZ0.02) and the log transformation of DHEAS (ORZ0.58; CI 95% GFR, glomerular filtration rate; WBC, white blood cell; HOMA-IR, homeostasis 0.37–0.92, PZ0.022). model assessment index for insulin resistance; hsCRP, high-sensitivity C-reactive protein; NT-proBNP, N-terminal pro-brain natriuretic peptide; T3, triiodothyronine; T4, total tetraiodothyronine. hypertension, 50.4% had ischemic etiology, 42.8% had Discussion previous myocardial infarction, and 27.1% were classified as functional class NYHA III–IV. Mean LVEF In this study, we have shown for the first time that low was 28.3G7.9% and mean 6 min walking distance was T3 levels, a strong indicator of poor prognosis in HF, are associated with lower BIA phase angle (a marker of 293G140 mts. The vast majority of the patients used membrane damage) and lower DHEAS (expression of b-blockers (90.2%) and angiotensin-converting enzyme diminished anabolic status). The association was inhibitor (ACEI) and an angiotensin receptor blocker independent of the influence of other recognized (ARB), ACEI–ARB (80.4%). Approximately one-third of markers of HF such as age, weight loss, renal function, our patients (36.8%) were on amiodarone. or muscle mass. T3 values ranged from 0.57 to 1.68 ng/ml. Mean T3 NT-proBNP also appeared related to lower T levels, G 3 value was 1.03 0.20 ng/ml. with significantly higher levels in group 1 patients. NT-proBNP levels are used for screening, diagnosis of Comparison of groups acute HF, and to establish prognosis in HF. Higher levels imply a worse outcome (23). It has previously been The cutoff point between groups 1 and 2 was shown that free T3 is significantly related to NT-proBNP 0.95 ng/ml. in patients with cardiovascular disease. Moreover, both Tables 1 and 2 show the comparison of measured parameters exert an independent and additively prog- parameters between groups. Group 1 patients (low T3 nostic value for mortality in HF (24, 25). In agreement values) were significantly older, with higher use of with these studies, as previously mentioned, we also

Table 3 Variables significantly associated with the lower T3 tertile in univariate and multiple logistic regressions.

Simple logistic regression Multiple logistic regression

Variables OR CI 95% P OR CI 95% P

Age (years) 1.05 1.01–1.09 0.004 0.98 0.93–1.03 0.51 Functional class III–IV 1.87 0.85–4.12 0.11 1.29 0.50–3.28 0.59 Amiodarone use 1.87 0.89–3.92 0.09 1.65 0.68–3.98 0.26 6 min walking test (mts) 0.996 0.993–0.999 0.008 0.999 0.995–1.003 0.72 GFR (ml/min/1.73 m2) 0.96 0.94–0.98 0.003 0.97 0.95–1.00 0.15 DHEAS log value 0.50 0.31–0.80 0.004 0.56 0.32–0.97 0.04 NT-proBNP log value 1.64 1.19–2.27 0.003 1.09 0.72–1.64 0.68 Adiponectin (mg/ml) 1.07 1.02–1.11 0.004 1.03 0.97–1.09 0.26 Low phase angle 3.18 1.51–6.72 0.002 2.95 1.16–7.50 0.02

CI, confidence interval; OR, odds ratio; GFR, glomerular filtration rate; NT-proBNP, N-terminal pro-brain natriuretic peptide.

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Downloaded from Bioscientifica.com at 09/28/2021 02:09:36PM via free access EUROPEAN JOURNAL OF ENDOCRINOLOGY (2011) 164 Low T3 levels in heart failure 941 found higher levels of NT-proBNP in patients with lower damage could partially explain a more advanced HF levels of T3. status among patients with low T3 levels. A novel association between low T3 levels in HF and the adrenal steroid DHEAS was revealed in this study. Declaration of interest It has previously been reported that plasma levels of DHEA are decreased in patients with HF (26) and that The authors declare that there is no conflict of interest that could they can be used as a prognostic marker of bad outcome be perceived as prejudicing the impartiality of the research reported. in HF (27). Although alternative explanations for the lower levels of this anabolic hormone in HF have been Funding offered (28, 29), lower DHEAS levels in HF could also be This research did not receive any specific grant from any funding interpreted in the light of a hypothyroid state. Lower agency in the public, commercial, or not-for-profit sector. DHEAS levels have previously been reported in hypothyroid women (30). It has been suggested that the lower concentrations of DHEA and DHEAS in hypothyroidism could be explained by decreased adrenal steroidogenesis (31). Moreover, an indirect References regulation by of human DHEA 1 Wartofsky L & Burman KD. Alterations in thyroid function in sulfotransferase family 1A member 2 (SULT2A1), the patients with systemic illness: the "euthyroid sick syndrome". enzyme that catalyzes sulfonation of DHEA to DHEAS Endocrine Reviews 1982 3 164–217. (doi:10.1210/edrv-3-2-164) has been reported and could also be playing a role in 2 DeGroot LJ. "Non-thyroidal illness syndrome" is functional central hypothyroidism, and if severe, hormone replacement is appro- lower DHEAS levels described in hypothyroidism (32). priate in light of present knowledge. Journal of Endocrinological On the other hand, given that oxidative stress is present Investigation 2003 26 1163–1170. in hypothyroid patients (33), lower DHEAS levels found 3 Peeters RP, Debaveye Y, Fliers E & Visser TJ. Changes within the in our low T3 patients could also be explained through thyroid axis during critical illness. Critical Care Clinics 2006 22 a decrease in 17,20-lyase activity. 41–55. (doi:10.1016/j.ccc.2005.08.006) 4 Ascheim DD & Hryniewicz K. Thyroid hormone in We evaluated body composition using whole-body patients with congestive heart failure: the low triiodothyronine BIA method and found that the chances of pertaining to state. Thyroid 2002 12 511–515. (doi:10.1089/105072502760 the low T3 group increased nearly three times when 143908) phase angle was low. A lower phase angle implies cell 5 Iervasi G, Pingitore A, Landi P, Raciti M, Ripoli A, Scarlattini M, death or decreased cell integrity (34). With regard to HF, L’Abbate A & Donato L. Low-T3 syndrome: a strong prognostic predictor of death in patients with heart disease. Circulation 2003 it has been described that bioimpedance phase angles 107 708–713. (doi:10.1161/01.CIR.0000048124.64204.3F) are lower in patients with functional class NYHA III–IV 6 Pingitore A, Landi P, Taddei MC, Ripoli A, L’Abbate A & Iervasi G. compared with those with NYHA I–II (35).In Triiodothyronine levels for risk stratification of patients with agreement with our findings, a smaller phase angle chronic heart failure. American Journal of 2005 118 after 6 months of follow-up was observed in HF patients 132–136. (doi:10.1016/j.amjmed.2004.07.052) 7 Rouf R, Greytak S, Wooten EC, Wu J, Boltax J, Picard M, who developed some alteration in the thyroid profile Svensson EC, Dillmann WH, Patten RD & Huggins GS. Increased when compared with the rest of the cohort (36). FOG-2 in failing myocardium disrupts thyroid hormone-dependent A limitation of our study is the high use of SERCA2 gene transcription. Circulation Research 2008 103 amiodarone found in the low T3 group. Due to its big 493–501. (doi:10.1161/CIRCRESAHA.108.181487) load, amiodarone can decrease conversion of T 8 Kinugawa K, Yonekura K, Ribeiro RC, Eto Y, Aoyagi T, Baxter JD, 4 Camacho SA, Bristow MR, Long CS & Simpson PC. Regulation to T3 yielding low serum T3 levels. However, to discard of isoforms in physiological and its possible effects as a confounder, amiodarone use, pathological cardiac hypertrophy. Circulation Research 2001 89 together with other parameters such as age, that has 591–598. (doi:10.1161/hh1901.096706) been also reportedly associated with lower T3 values, 9 Ojamaa K, Kenessey A, Shenoy R & Klein I. Thyroid hormone was adjusted within the multivariable analysis and was metabolism and cardiac gene expression after acute myocardial infarction in the rat. American Journal of . Endocrinology not independently related to low T3 levels. Furthermore, and Metabolism 2000 279 E1319–E1324. our group of patients with the lowest T3 levels was in a 10 Simonides WS, Mulcahey MA, Redout EM, Muller A, Zuidwijk MJ, more advanced HF status and this is in line with authors Visser TJ, Wassen FW, Crescenzi A, da-Silva WS, Harney J, that reported that concomitant amiodarone therapy Engel FB, Obregon MJ, Larsen PR, Bianco AC & Huang SA. does not have a relevant influence in the higher Hypoxia-inducible factor induces local thyroid hormone inacti- vation during hypoxic–ischemic disease in rats. Journal of Clinical mortality rate found in HF patients with low T3 (37). Investigation 2008 118 975–983. (doi:10.1172/JCI32824) On the other hand, the strengths of this study lie on 11 Olivares EL, Marassi MP, Fortunato RS, da Silva AC, Costa- the multiplicity of metabolic and neurohormonal e-Sousa RH, Araujo IG, Mattos EC, Masuda MO, Mulcahey MA, parameters included. The reported findings are original Huang SA, Bianco AC & Carvalho DP. Thyroid function and should be considered hypothesis generating. disturbance and type 3 induction after myocardial infarction in rats a time course study. Endocrinology In conclusion, we have found that low T3 levels in HF 2007 148 4786–4792. (doi:10.1210/en.2007-0043) patients are associated with several markers of illness. 12 Henderson KK, Danzi S, Paul JT, Leya G, Klein I & Samarel AM. Lower anabolic activity and more severe membrane Physiological replacement of T3 improves left ventricular function

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in an animal model of myocardial infarction-induced congestive 26 Anker SD, Chua TP, Ponikowski P, Harrington D, Swan JW, heart failure. Circulation. Heart Failure 2009 2 243–252. (doi:10. Kox WJ, Poole-Wilson PA & Coats AJ. Hormonal changes and 1161/CIRCHEARTFAILURE.108.810747) catabolic/anabolic imbalance in chronic heart failure and their 13 Forini F, Lionetti V, Ardehali H, Pucci A, Cecchetti F, Ghanefar M, importance for cardiac cachexia. Circulation 1997 96 526–534. Nicolini G, Ichikawa Y, Nannipieri M, Recchia FA & Iervasi G. Early 27 Jankowska EA, Biel B, Majda J, Szklarska A, Lopuszanska M, long-term L-T3 replacement rescues mitochondria and prevents Medras M, Anker SD, Banasiak W, Poole-Wilson PA & ischemic cardiac remodeling in rats. Journal of Cellular and Ponikowski P. Anabolic deficiency in men with chronic heart Molecular Medicine 2010 15 514–524. (doi:10.1111/j.1582- failure: prevalence and detrimental impact on survival. Circulation 4934.2010.01014.x) 2006 114 1829–1837. (doi:10.1161/CIRCULATIONAHA.106. 14 Klein I & Danzi S. Thyroid hormone treatment to mend a broken 649426) heart. Journal of Clinical Endocrinology and Metabolism 2008 93 28 Moriyama Y, Yasue H, Yoshimura M, Mizuno Y, Nishiyama K, 1172–1174. (doi:10.1210/jc.2008-0291) Tsunoda R, Kawano H, Kugiyama K, Ogawa H, Saito Y & Nakao K. 15 Hamilton MA, Stevenson LW, Fonarow GC, Steimle A, The plasma levels of sulfate are decreased Goldhaber JI, Child JS, Chopra IJ, Moriguchi JD & Hage A. Safety in patients with chronic heart failure. Journal of Clinical and hemodynamic effects of intravenous triiodothyronine in Endocrinology and Metabolism 2000 85 1834–1840. (doi:10. advanced congestive heart failure. American Journal of Cardiology 1210/jc.85.5.1834) 1998 81 443–447. (doi:10.1016/S0002-9149(97)00950-8) 29 Nawata H, Ohashi M, Haji M, Takayanagi R, Higuchi K, Fujio N, 16 Pingitore A, Galli E, Barison A, Iervasi A, Scarlattini M, Nucci D, Hashiguchi T, Ogo A, Nakao R, Ohnaka K & Nishi Y. Atrial and L’Abbate A, Mariotti R & Iervasi G. Acute effects of triiodothy- brain natriuretic peptide in adrenal steroidogenesis. Journal of ronine replacement therapy in patients with chronic heart failure Steroid Biochemistry and Molecular Biology 1991 40 367–379. and low-T3 syndrome: a randomized, placebo-controlled study. (doi:10.1016/0960-0760(91)90204-I) Journal of Clinical Endocrinology and Metabolism 2008 93 30 Bassi F, Pupi A, Giannotti P, Fiorelli G, Forti G, Pinchera A & 1351–1358. (doi:10.1210/jc.2007-2210) Serio M. Plasma dehydroepiandrosterone sulphate in hypothyroid 17 Lubrano V, Pingitore A, Carpi A & Iervasi G. Relationship between premenopausal women. Clinical Endocrinology 1980 13 111–113. triiodothyronine and proinflammatory cytokines in chronic heart (doi:10.1111/j.1365-2265.1980.tb01031.x) failure. Biomedicine and Pharmacotherapy 2010 64 165–169. 31 Tagawa N, Tamanaka J, Fujinami A, Kobayashi Y, Takano T, (doi:10.1016/j.biopha.2009.09.001) Fukata S, Kuma K, Tada H & Amino N. Serum dehydroepian- 18 Packer M. The neurohormonal hypothesis: a theory to explain the drosterone, dehydroepiandrosterone sulfate, and pregnenolone mechanism of disease progression in heart failure. Journal of the sulfate concentrations in patients with hyperthyroidism and American College of Cardiology 1992 20 248–254. (doi:10.1016/ hypothyroidism. Clinical Chemistry 2000 46 523–528. 0735-1097(92)90167-L) 32 Huang YH, Lee CY, Tai PJ, Yen CC, Liao CY, Chen WJ, Liao CJ, 19 Tsutamoto T, Wada A, Maeda K, Hisanaga T, Maeda Y, Fukai D, Cheng WL, Chen RN, Wu SM, Wang CS & Lin KH. Indirect Ohnishi M, Sugimoto Y & Kinoshita M. Attenuation of regulation of human dehydroepiandrosterone sulfotransferase compensation of endogenous cardiac natriuretic peptide system family 1A member 2 by thyroid hormones. Endocrinology 2006 in chronic heart failure: prognostic role of plasma brain natriuretic 147 2481–2489. (doi:10.1210/en.2005-1166) peptide concentration in patients with chronic symptomatic left 33 Torun AN, Kulaksizoglu S, Kulaksizoglu M, Pamuk BO, Isbilen E & ventricular dysfunction. Circulation 1997 96 509–516. Tutuncu NB. Serum total antioxidant status and lipid peroxidation 20 Kistorp C, Faber J, Galatius S, Gustafsson F, Frystyk J, marker malondialdehyde levels in overt and subclinical hypothy- Flyvbjerg A & Hildebrandt P. Plasma adiponectin, body mass roidism. Clinical Endocrinology 2009 70 469–474. (doi:10.1111/ index, and mortality in patients with chronic heart failure. j.1365-2265.2008.03348.x) Circulation 2005 112 1756–1762. (doi:10.1161/CIRCULATIO- 34 Selberg O & Selberg D. Norms and correlates of bioimpedance NAHA.104.530972) phase angle in healthy human subjects, hospitalized patients, 21 Thierer J, Acosta A, Vainstein N, Sultan M, Francesia A, Marino J, and patients with liver cirrhosis. European Journal of Applied Prado AH, Guglielmone R, Trivi M, Boero L, Brites F & Anker S. Physiology 2002 86 509–516. (doi:10.1007/s00421-001- Relation of left ventricular ejection fraction and functional 0570-4) capacity with metabolism and inflammation in chronic heart 35 Castillo Martı´nez L, Colı´n Ramı´rez E, Orea Tejeda A, Asensio failure with reduced ejection fraction (from the MIMICA Study). Lafuente E, Bernal Rosales LP, Rebollar Gonza´lez V, Narva´ez American Journal of Cardiology 2010 105 977–983. (doi:10.1016/ David R & Dorantes Garcı´a J. Bioelectrical impedance and strength j.amjcard.2009.11.017) measurements in patients with heart failure: comparison with 22 Baumgartner RN, Chumlea WC & Roche AF. Bioelectric functional class. Nutrition 2007 23 412–418. (doi:10.1016/j.nut. impedance phase angle and body composition. American 2007.02.005) Journal of Clinical Nutrition 1988 48 16–23. 36 Silva-Tinoco R, Castillo-Martı´nez L, Orea-Tejeda A, Orozco- 23 Bhalla V, Willis S & Maisel AS. B-type natriuretic peptide: the level Gutie´rrez JJ, Va´zquez-Dı´az O, Montan˜o-Herna´ndez P, Flores- and the drug – partners in the diagnosis of congestive heart Rebollar A & Reza-Albarra´n A. Developing thyroid disorders is failure. Congestive Heart Failure 2004 10 3–27. (doi:10.1111/ associated with poor prognosis factors in patient with stable j.1527-5299.2004.03310.x) chronic heart failure. International Journal of Cardiology 2009 147 24 Passino C, Pingitore A, Landi P, Fontana M, Zyw L, Clerico A, e24–e25. (doi:10.1016/j.ijcard.2009.01.012) Emdin M & Iervasi G. Prognostic value of combined measurement 37 Coceani M, Molinaro S, Scalese M, Landi P, Carpeggiani C, of brain natriuretic peptide and triiodothyronine in heart failure. L’abbate A, Iervasi G & Pingitore A. Thyroid hormone, amiodarone Journal of Cardiac Failure 2009 15 35–40. (doi:10.1016/j.cardfail. therapy, and prognosis in left ventricular systolic dysfunction. 2008.08.008) Journal of Endocrinological Investigation 2011 In press. (doi:10.3275/ 25 Pfister R, Strack N, Wielckens K, Malchau G, Erdmann E & 7351) Schneider CA. The relationship and prognostic impact of low-T3 syndrome and NT-pro-BNP in cardiovascular patients. International Journal of Cardiology 2009 144 187–190 (doi: 10.1016/j.ijcard.2009.03.137). (doi:10.1016/j.ijcard.2009. Received 15 March 2011 03.137) Accepted 31 March 2011

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